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Role of PCSK9 inhibition during the inflammatory
stage of SARS-COV-2: an updated review
Hina Arsha,FNU Manoj Kumarb,FNU Simran
AQ1 b,Sweta Tamangg,Mahboob ur Rehmanc,Gulfam Ahmede,
Masood Khanf,Jahanzeb Malikd,Amin Mehmoodih,*
Abstract
The potential role of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in the management of COVID-19 and other
medical conditions has emerged as an intriguing area of research. PCSK9 is primarily known for its impact on cholesterol meta-
bolism, but recent studies have unveiled its involvement in various physiological processes, including inflammation, immune reg-
ulation, and thrombosis. In this abstract, the authors review the rationale and potential implications of PCSK9 inhibition during the
inflammatory stage of SARS-CoV-2 infection. Severe cases of COVID-19 are characterized by an uncontrolled inflammatory
response, often referred to as the cytokine storm, which can lead to widespread tissue damage and organ failure. Preclinical studies
suggest that PCSK9 inhibition could dampen this inflammatory cascade by reducing the production of pro-inflammatory cytokines.
Additionally, PCSK9 inhibition may protect against acute respiratory distress syndrome (ARDS) through its effects on lung injury and
inflammation. COVID-19 has been linked to an increased risk of cardiovascular complications, especially in patients with pre-existing
cardiovascular conditions or dyslipidemia. PCSK9 inhibitors are known for their ability to lower low-density lipoprotein (LDL) cho-
lesterol levels by enhancing the recycling of LDL receptors in the liver. By reducing LDL cholesterol, PCSK9 inhibition might protect
blood vessels from further damage and lower the risk of atherosclerotic plaque formation. Moreover, PCSK9 inhibitors have shown
potential antithrombotic effects in preclinical studies, making them a potential avenue to mitigate the increased risk of coagulation
disorders and thrombotic events observed in COVID-19. While the potential implications of PCSK9 inhibition are promising, safety
considerations and possible risks need careful evaluation. Hypocholesterolemia, drug interactions, and long-term safety are some of
the key concerns that should be addressed. Clinical trials are needed to establish the efficacy and safety of PCSK9 inhibitors in
COVID-19 patients and to determine the optimal timing and dosing for treatment. Future research opportunities encompass
investigating the immune response, evaluating long-term safety, exploring combination therapy possibilities, and advancing per-
sonalized medicine approaches. Collaborative efforts from researchers, clinicians, and policymakers are essential to fully harness the
therapeutic potential of PCSK9 inhibition and translate these findings into meaningful clinical outcomes.
Keywords: cardiovascular protection, COVID-19, inflammation, PCSK9 inhibition, thrombosis
Introduction
The COVID-19 pandemic caused by the SARS-CoV-2 has led to
significant morbidity
AQ3 and mortality worldwide
[1]
. One of the
most severe complications of COVID-19 is acute respiratory
distress syndrome (ARDS) and systemic inflammation, which can
escalate into a potentially life-threatening cytokine storm
[2]
. The
extent of immune dysregulation is a crucial determinant of
patient outcomes, with greater dysregulation associated with
worse prognoses and increased mortality. In this context, tar-
geting key components of the inflammatory response during
COVID-19 holds promising potential for effective therapeutic
interventions, especially for critically ill patients
[3]
. Among the
various inflammatory drivers in COVID-19, interleukin (IL)-6
has emerged as a major contributor, with elevated levels of IL-6
being predictive of a more severe disease course
[4]
. Proprotein
convertase subtilisin/kexin type 9 (PCSK9) is an enzyme known
for its role in regulating low-density lipoprotein (LDL) receptors,
and it has been associated with vascular inflammation
[5]
. During
acute inflammation, there is an accumulation of oxidized LDL
and apolipoprotein B, which leads to the generation of cholesterol
crystals in macrophages. These cholesterol crystals activate the
inflammasome complex, triggering the release of inflammatory
cytokines. Interestingly, PCSK9 has been shown to directly acti-
vate pro-inflammatory signalling pathways, leading to increased
cytokine production
[6]
. Recent studies have also highlighted the
impact of PCSK9 on the immune response in patients with
septic shock, wherein lower PCSK9 function was associated
with reduced inflammatory responses and improved overall
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a
Department of Medicine, THQ Hospital, Pasrur,
b
Department of Medicine, Jinnah
Sindh Medical College, Karachi,
c
Department of Cardiology, Pakistan Institute of
Medical Sciences,
d
Department of Cardiovascular Medicine, Cardiovascular
Analytics Group, Islamabad,
e
Department of Medicine, Muhammad Hospital,
Lahore,
f
Department of Cardiology, Armed Forces Institute of Cardiology,
Rawalpindi, Pakistan,
g
Department of Medicine, Nepal Medical College and
Teaching Hospital, Kathmandu, Nepal and
h
Department of Medicine, Ibn e Seena
Hospital, Kabul, Afghanistan
Sponsorships or competing interests that may be relevant to content are disclosed at
the end of this article.
Published online ■■
*Correspondi
AQ2 ng author. Address: Department of Medicine, Ibn e Seena Hospital,
Kabul, Afghanistan. E-mail: amin.doctor21@gmail.com (A. Mehmoodi).
Received 16 September 2023; Accepted 28 November 2023
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. This is an
open access article distributed under the Creative Commons Attribution License 4.0
(CCBY), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Annals of Medicine & Surgery (2023) 00:000–000
http://dx.doi.org/10.1097/MS9.0000000000001601
’
Review
1
outcomes
[7]
. Additionally, individuals with a loss-of-function
genotype for PCSK9 have shown lower PCSK9 levels and
enhanced resolution of infections. Given the potential influence of
PCSK9 on inflammatory pathways and its role in lipid metabo-
lism, researchers have explored the use of PCSK9 inhibitors as
potential therapeutic agents in COVID-19
[8]
. PCSK9 inhibitors
are potent lipid-lowering drugs known to reduce LDL cholesterol
(LDL-C) levels, and they may also have direct effects on PCSK9-
mediated inflammatory pathways
[9]
. Both experimental and
clinical evidence suggest that PCSK9 inhibitors could exert anti-
inflammatory effects by interfering with the IL-6–mediated
inflammatory pathway triggered by PCSK9
[10]
. These findings
have sparked interest in investigating the role of PCSK9 inhibi-
tion as a potential treatment strategy during the inflammatory
stage of SARS-CoV-2 infection. In this updated review, we aim to
delve into the current understanding of the role of PCSK9 inhi-
bition in mitigating the inflammatory response during COVID-
19. By examining the experimental and clinical evidence, we seek
to explore the potential benefits of PCSK9 inhibitors as a novel
therapeutic approach in managing the inflammatory complica-
tions of SARS-CoV-2 infection, with a focus on critically ill
patients. As the global health community continues its relentless
efforts to combat the COVID-19 pandemic, a comprehensive
assessment of the role of PCSK9 inhibition in modulating the
immune response may provide valuable insights into the devel-
opment of more effective treatment strategies for severe cases of
COVID-19.
Methods
A comprehensive literature search was conducted to identify
relevant studies on the role of PCSK9 inhibition during the
inflammatory stage of SARS-CoV-2 infection. Electronic data-
bases, including PubMed, Embase, Scopus, and Web of Science,
were searched. The search terms included combinations of key-
words related to PCSK9, COVID-19, inflammation, cytokine
storm, IL-6, and PCSK9 inhibitors. The search was restricted to
studies published in English up to the date of the search, with a
focus on articles published within the last 2 years. Two inde-
pendent reviewers screened the search results for eligibility based
on predefined inclusion and exclusion criteria. Inclusion criteria
included studies investigating the impact of PCSK9 inhibition on
the inflammatory response during COVID-19, both experimental
and clinical studies. Studies assessing PCSK9 inhibitors in other
inflammatory conditions were also considered if they provided
mechanism of PCSK9 inhibition on inflammation and immune
regulation. Data from the selected studies were independently
extracted by two reviewers using a standardized data extraction
form. The was presented in the form of narrative synthesis.
PCSK9 function
PCSK9 plays a crucial role in regulating cholesterol metabolism,
specifically through its impact on the expression and function of
the LDLR
[11]
. Disruptions in PCSK9 activity can significantly
affect plasma cholesterol levels, contributing to the development
of cardiovascular diseases (CVD)
[12]
. PCSK9 is encoded by the
PCSK9 gene found on chromosomes 1p32.3 in humans and 4C7
in mice
[13]
. The gene consists of thirteen exons encoding a 692-
amino acid PCSK9 protein in humans and twelve exons encoding
a 694-amino acid PCSK9 protein in mice
[14]
. Additionally,
PCSK9 shows high conservation across various mammalian
species, suggesting its vital role in cholesterol regulation. The
PCSK9 protein comprises four main domains: the signal peptide,
prodomain, catalytic domain, and C-terminal domain
[15]
. During
its maturation, PCSK9 undergoes autocleavage by its catalytic
domain, generating the mature enzyme. The prodomain is
necessary for PCSK9’s maturation and secretion, as it associates
with the catalytic domain and inhibits its activity. PCSK9 pri-
marily acts as a negative regulator of LDLR by binding to it on the
cell surface and facilitating its internalization
[16]
. Once inter-
nalized, the PCSK9-LDLR complex remains in acidic endosomes,
preventing LDLR recycling and targeting it for lysosomal
degradation
[17]
. This leads to reduced LDL-C clearance from the
bloodstream and elevated plasma LDL-C levels. Apart from the
liver, PCSK9 is expressed in various extra-hepatic tissues, such as
vascular smooth muscle cells, macrophages, endothelial cells,
pancreatic beta cells, and the central nervous system
[18]
. Its
function in these tissues may vary, indicating cell and tissue-
specific roles. PCSK9 also affects triglyceride-rich lipoproteins,
such as very VLDL and chylomicrons
[19]
. It can influence the
production and secretion of VLDL and modulate the metabolism
of intestinal chylomicrons, though its impact on plasma trigly-
ceride levels is relatively modest compared to its effect on LDL-C.
PCSK9 has garnered significant interest in its role in regulating
lipoprotein(a) (Lp(a)), a lipoprotein-associated with an increased
risk of CVD
[20]
. Inhibition of PCSK9 has been found to reduce
plasma Lp(a) levels, providing a potential therapeutic avenue for
managing elevated Lp(a) and lowering CVD risk
[21]
. PCSK9’s
actions on lipoprotein metabolism involve a complex interplay
between its extracellular and intracellular pathways. The extra-
cellular pathway predominantly regulates LDLR-mediated cata-
bolism, while the intracellular pathway can modulate apoB
secretion, impacting VLDL and chylomicron metabolism
[22]
.
PCSK9’s role in LDLR regulation
PCSK9-LDLR binding and endocytosis are crucial steps in
PCSK9’s role as a regulator of cholesterol metabolism
[16]
. The
interaction between PCSK9 and LDLR on the cell surface is a
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HIGHLIGHTS
•The potential role of proprotein convertase subtilisin/kexin
type 9 (PCSK9) inhibition in the management of COVID-
19 and other medical conditions has emerged as an
intriguing area of research.
•PCSK9 is primarily known for its impact on cholesterol
metabolism, but recent studies have unveiled its involve-
ment in various physiological processes, including inflam-
mation, immune regulation, and thrombosis.
•Preclinical studies suggest that PCSK9 inhibition could
dampen this inflammatory cascade by reducing the pro-
duction of pro-inflammatory cytokines.
•PCSK9 inhibitors have shown potential antithrombotic
effects in preclinical studies, making them a potential
avenue to mitigate the increased risk of coagulation
disorders and thrombotic events observed in COVID-19.
•Clinical trials are needed to establish the efficacy and safety
of PCSK9 inhibitors in COVID-19 patients and to deter-
mine the optimal timing and dosing for treatment.
Arsh et al. Annals of Medicine & Surgery (2023) Annals of Medicine & Surgery
2
highly specific and tightly regulated process that influences LDL-
C clearance and plasma cholesterol levels. The binding of PCSK9
to LDLR occurs through specific domains on both proteins.
PCSK9 possesses a catalytic domain that plays a critical role in
recognizing and binding to the LDLR
[23]
. Meanwhile, LDLR
contains an epidermal growth factor precursor homology
domain A (EGF-A), which serves as the binding site for PCSK9.
The process of binding begins with the recognition of LDLR by
PCSK9 through the interaction of their respective domains
[24]
.
This interaction is characterized by specific amino acid residues in
the catalytic domain of PCSK9, which align with complementary
residues in the EGF-A domain of LDLR. Following the binding of
PCSK9 to LDLR, the complex is internalized into the cell through
endocytosis. Endocytosis is a cellular process that involves the
invagination of the cell membrane, leading to the formation of
vesicles containing extracellular materials, including the PCSK9-
LDLR complex
[25]
. The process of endocytosis allows the cell to
internalize and transport various molecules from the cell surface
to the intracellular compartments. In the context of PCSK9 and
LDLR, endocytosis is a critical mechanism for regulating LDLR
levels on the cell surface and determining the fate of LDLR in
cholesterol metabolism. Once internalized, the PCSK9-LDLR
complex is transported through the endosomal network within
the cell. The complex eventually reaches acidic endosomes, which
are compartments characterized by their low pH environment.
The acidic pH of the endosomes triggers conformational changes
in the PCSK9-LDLR complex, facilitating the dissociation of
PCSK9 from LDLR. This release of PCSK9 from LDLR is a
crucial step that sets the stage for further LDLR regulation
[26]
.
Upon dissociation from PCSK9, LDLR can take one of two paths
within the endosomal system: recycling back to the cell surface or
being directed to lysosomes for degradation. In the absence of
PCSK9, LDLR typically undergoes recycling, allowing it to return
to the cell surface and continue its role in capturing LDL-C from
the bloodstream. However, in the presence of PCSK9, recycling is
inhibited, and LDLR is targeted for lysosomal degradation
[27]
.
The PCSK9-LDLR complex in acidic endosomes is recognized by
lysosomal targeting signals, leading to the recruitment of lyso-
somal enzymes
[28]
. These enzymes promote the ubiquitination of
LDLR, marking it for degradation within the lysosomes. The
degradation of LDLR in lysosomes, facilitated by PCSK9, results
in a reduction of LDLR available on the cell surface. This reduced
LDLR expression decreases the uptake and clearance of LDL-C
particles from the bloodstream, leading to elevated plasma LDL-
C levels. As a consequence, dysregulated PCSK9 activity can
contribute to hypercholesterolaemia and increase the risk of
developing cardiovascular diseases, such as atherosclerosis and
coronary artery disease
[29]
.
Rationale for PCSK9 inhibition during SARS-CoV-2 infection
The rationale for PCSK9 inhibition during SARS-CoV-2 infection
stems from the interplay between lipid metabolism, inflamma-
tion, and cardiovascular complications observed in COVID-19
patients. PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9)
is a protein primarily known for its role in regulating cholesterol
levels by promoting the degradation of LDLRs in the liver.
However, recent research has uncovered additional functions of
PCSK9 that go beyond lipid metabolism, indicating its potential
involvement in inflammatory processes and immune responses.
Dyslipidemia and COVID-19
Dyslipidemia is a com AQ4
mon metabolic disorder characterized by
abnormal levels of lipids in the bloodstream. It can involve ele-
vated levels of LDL-C, and triglycerides, as well as reduced levels
of HDL-C
[30]
. These lipid imbalances can lead to the development
of atherosclerosis, a condition where plaque buildup occurs on
the inner walls of arteries. COVID-19 can directly impact the
cardiovascular system, leading to a range of cardiovascular
complications. The virus can infect endothelial cells that line the
blood vessels, causing endothelial dysfunction, inflammation,
and damage
[31]
. This process can trigger a cascade of events,
including platelet activation, coagulation abnormalities, and the
formation of blood clots. The combination of viral effects and
systemic inflammation can exacerbate existing cardiovascular
conditions, such as dyslipidemia and atherosclerosis, leading to
increased cardiovascular risk in COVID-19 patients
[32]
.
Dyslipidemia has been associated with an increased risk of severe
COVID-19 outcomes. Elevated LDL cholesterol levels are con-
sidered a major risk factor for atherosclerotic plaque formation.
The presence of underlying atherosclerosis can lead to unstable
plaques that are more prone to rupture, resulting in acute cardi-
ovascular events, such as heart attacks or strokes, in COVID-19
patients
[33]
. Moreover, dyslipidemia may contribute to an
excessive inflammatory response to COVID-19. Dyslipidemia
can activate immune cells and promote the release of pro-
inflammatory cytokines, thereby exacerbating the cytokine storm
observed in severe cases of COVID-19
[34]
. This hyperin-
flammatory state can lead to a vicious cycle of tissue damage and
inflammation, further increasing the risk of cardiovascular
complications.
Optimal management of dyslipidemia is essential to reduce the
risk of cardiovascular complications in COVID-19 patients
[35]
.
Some studies suggest that statins might have a beneficial impact
on COVID-19 outcomes by dampening the inflammatory
response
[36]
. However, more research is needed to establish a
definitive link between statin use and COVID-19 outcomes. In
COVID-19 patients with dyslipidemia, managing cardiovascular
risk requires a comprehensive and individualized approach.
However, there are challenges in ensuring optimal lipid man-
agement during the pandemic. Access to healthcare services may
be limited due to overwhelming demands on healthcare systems,
and some patients may be hesitant to seek medical care due to
infection concerns
[37]
. Additionally, potential drug interactions
and safety considerations should be carefully evaluated when
prescribing lipid-lowering medications to COVID-19 patients
receiving other treatments or therapies.
PCSK9 and inflammation
Several studies have indicated that PCSK9 can influence the
inflammatory milieu through various mechanisms
[38]
. One key
observation is that PCSK9 promotes the production of pro-
inflammatory cytokines, including interleukin-6 (IL-6) and
tumour necrosis factor-alpha (TNF-alpha)
[39]
. These cytokines
are crucial mediators of the immune response and play significant
roles in initiating and sustaining inflammation. For instance, a
study found that PCSK9 expression was increased in the aortic
tissues of mice exposed to a high-fat diet
[40]
. This upregulation of
PCSK9 was associated with increased levels of pro-inflammatory
cytokines, suggesting a potential link between PCSK9 and
inflammation in the context of atherosclerosis, a chronic
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3
inflammatory condition. Beyond its effects on cytokine produc-
tion, PCSK9 may also impact immune cell function
[41]
. Immune
cells play a central role in orchestrating the immune response
during infections and inflammatory conditions. Studies have
shown that PCSK9 can influence the differentiation and activa-
tion of immune cells, such as T cells and macrophages
[42]
. This
suggests that PCSK9 may promote the recruitment and activation
of pro-inflammatory immune cells, contributing to the inflam-
matory environment in atherosclerosis. Considering the role of
PCSK9 in inflammation and immune responses, it is reasonable to
explore its potential relevance in the context of viral infections,
including COVID-19. In COVID-19, the immune response is a
critical determinant of disease severity
[43]
. The virus can trigger a
dysregulated immune response characterized by an excessive
release of pro-inflammatory cytokines, known as the cytokine
storm
[44]
. This immune dysregulation contributes to tissue
damage, organ dysfunction, and severe clinical outcomes in some
COVID-19 patients. As PCSK9 has been linked to the production
of pro-inflammatory cytokines, it is possible that PCSK9 may
contribute to the cytokine storm observed in severe COVID-19
cases. Targeting PCSK9 could be a potential strategy to modulate
the inflammatory response and potentially alleviate the severity of
COVID-19
[45]
. The growing understanding of PCSK9’s role in
inflammation and immune responses opens up potential ther-
apeutic implications. In addition to its established role in cho-
lesterol metabolism, PCSK9 inhibitors might have additional
benefits in certain inflammatory conditions, including athero-
sclerosis and potentially COVID-19. However, it is essential to
approach the use of PCSK9 inhibitors cautiously, considering the
complexity of immune responses and potential off-target effects.
Further research, including clinical trials, is necessary to explore
the safety and efficacy of PCSK9 inhibitors as immunomodula-
tory agents in various inflammatory conditions, including
COVID-19.
Enhanced inflammatory response in COVID-19
The inflammatory response plays a critical role in the body’s
defense against infections. However, in some severe cases of
COVID-19, the immune response becomes dysregulated, leading
to an exaggerated and uncontrolled release of pro-inflammatory
cytokines, commonly referred to as a cytokine storm
[46]
. This
cytokine storm is a key contributor to the development of ARDS
and multi-organ failure, two of the most severe and life-threa-
tening complications of COVID-19
[47]
. The cytokine storm is
characterized by an overwhelming release of pro-inflammatory
cytokines, such as interleukin-6 (IL-6), tumour necrosis factor-
alpha (TNF-alpha), interleukin-1 beta (IL-1β), and others
[48]
.
This excessive cytokine production can lead to widespread
inflammation, tissue damage, and disruption of normal physio-
logical processes. In severe cases of COVID-19, the immune
system’s response to the SARS-CoV-2 virus can become dysre-
gulated, resulting in a massive and uncontrolled cytokine release.
This cytokine storm can cause severe damage to the lungs, leading
to ARDS, where the lungs become inflamed and filled with fluid,
severely impairing oxygen exchange
[49]
. Additionally, systemic
inflammation can lead to damage in other organs, including the
heart, kidneys, and liver, contributing to multi-organ failure
(Fig. 1). Recent studies have highlighted the involvement of
PCSK9 in the modulation of inflammation
[50]
. While PCSK9 is
primarily known for its role in cholesterol metabolism, emerging
evidence suggests that it also affects the immune system and
inflammatory processes. Studies have shown that PCSK9 can
promote the production of pro-inflammatory cytokines, includ-
ing IL-6 and TNF-alpha, in immune cells. A study demonstrated
that PCSK9 enhances the production of pro-inflammatory cyto-
kines in human macrophages, indicating a potential link between
PCSK9 and inflammation
[51]
.
Potential therapeutic benefits
By inhibiting PCSK9, we could not only improve lipid metabo-
lism but also modulate the inflammatory response in COVID-19
patients. Lowering LDL cholesterol levels through PCSK9 inhi-
bition might protect blood vessels from further damage, reducing
the risk of cardiovascular complications in COVID-19 patients
with dyslipidemia. Simultaneously, the suppression of PCSK9-
mediated inflammation might help attenuate the cytokine storm
and mitigate the severe immune response associated with
COVID-19.
Potential implications of PCSK9 in SARS-COV-2
PCSK9 inhibition during the inflammatory stage of SARS-CoV-2
infection could have several potential implications, ranging from
the modulation of the immune response to the protection of
cardiovascular health (Fig. 2).
Attenuation of the cytokine storm
PCSK9 can attenuate inflammation through various mecha-
nisms
[1]
. One of the key pathways is the regulation of LDLR
expression. PCSK9 binds to LDLRs and targets them for degra-
dation, reducing their availability on the cell surface. This, in
turn, leads to increased LDL cholesterol levels. However, when
PCSK9 is inhibited, LDLRs are protected from degradation,
resulting in enhanced LDL cholesterol clearance from the
blood
[52]
. Interestingly, LDLRs also play a role in immune cell
function. Macrophages, a type of immune cell, express LDLRs
and use them to internalize LDL particles. When LDLR expres-
sion is increased due to PCSK9 inhibition, macrophages take up
more LDL particles
[39]
. This process can lead to the production of
anti-inflammatory molecules and the suppression of pro-inflam-
matory cytokines. Additionally, PCSK9 inhibition might reduce
the expression of inflammatory molecules in endothelial cells
lining the blood vessels, further modulating the inflammatory
response. Some animal studies have provided insight into the
potential benefits of PCSK9 inhibition in the context of inflam-
mation and acute lung injury, which are relevant to COVID-
19
[33]
. Based on these preclinical findings, there is a hypothesis
that PCSK9 inhibition might have a beneficial impact on the
inflammatory stage of COVID-19
[25]
. By reducing pro-inflam-
matory cytokine production and promoting anti-inflammatory
responses, PCSK9 inhibition could potentially dampen the cyto-
kine storm, thereby mitigating the severity of the disease and
improving patient outcomes
[28]
. While the preclinical evidence is
promising, it is essential to note that the translation of findings
from animal studies to human patients can be complex.
Additionally, the inflammatory response to COVID-19 is highly
dynamic and influenced by various factors, including viral load,
host immune status, and genetic predisposition
[35]
. Therefore,
the efficacy of PCSK9 inhibition in COVID-19 patients needs
to be thoroughly evaluated in well-designed clinical trials.
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4
Furthermore, PCSK9 inhibitors are currently approved for
managing dyslipidemia, and their use in COVID-19 would
require careful consideration of potential drug interactions and
safety concerns. Clinical trials are necessary to determine the
optimal dosage, timing, and patient selection for PCSK9 inhibi-
tion in COVID-19.
Protection against ARDS
Emerging evidence suggests that PCSK9 may play a role in lung
injury and inflammation, making it a potential target for miti-
gating ARDS and alleviating respiratory distress in COVID-19
patients. Recent studies have revealed that PCSK9 is not only
involved in lipid metabolism but also has direct effects on lung
cells and the respiratory system
[53]
. PCSK9 receptors have been
found in the lung tissue, suggesting a possible role for PCSK9 in
lung function and homoeostasis. Some preclinical studies have
demonstrated that PCSK9 is implicated in lung inflammation and
injury. The exact mechanisms by which PCSK9 may contribute to
lung injury and inflammation are not fully understood. PCSK9
has been linked to the regulation of pro-inflammatory cytokines,
such as interleukin-1 beta (IL-1β) and interleukin-18 (IL-18)
[54]
.
These cytokines are known to play a significant role in the
initiation and progression of lung inflammation. PCSK9 inhibi-
tion may reduce the production of these pro-inflammatory
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Figure 1. Inflammatory response of COVID-19.
Figure 2. PCSK9 activates endosomal and cytoplasmic sensors, TLR3/7 and MAVS, respectively. These receptors activate interferon regulatory factors (IRFs) and
NFkB to induce inflammatory cytokines, including interferons (IFN). Dendritic cells (DCs) sample antigen and migrate to lymphoid organs to prime adaptive
immunity. CD8 T cells induce apoptosis after recognition of antigen on DCs or infected cells. PCSK9, proprotein convertase subtilisin/kexin type 9.
Arsh et al. Annals of Medicine & Surgery (2023)
5
cytokines, thereby attenuating lung inflammation and injury.
PCSK9 has been associated with increased oxidative stress, which
can contribute to tissue damage and inflammation
[55]
. By inhi-
biting PCSK9, it might be possible to reduce oxidative stress and
limit lung injury in COVID-19 patients. PCSK9 may influence
immune cell function in the lungs. Immune cells play a crucial role
in orchestrating the immune response during viral infections.
PCSK9 inhibition might modulate the immune response in a way
that promotes tissue repair and resolution of inflammation,
potentially protecting against ARDS
[56,57]
. Considering the
potential involvement of PCSK9 in lung injury and inflammation,
PCSK9 inhibition may hold promise as a therapeutic strategy to
protect against ARDS in severe COVID-19 cases. By reducing
lung inflammation, PCSK9 inhibition could help preserve lung
function and prevent the progression of respiratory failure. While
the preliminary evidence is encouraging, it is essential to
approach the potential use of PCSK9 inhibitors in COVID-19
with caution. ARDS in COVID-19 is a complex condition influ-
enced by various factors, and its pathogenesis involves a combi-
nation of viral effects, immune dysregulation, and patient-specific
factors.
Modulation of immune response
PCSK9 is not only involved in lipid metabolism but also in
immune cell regulation. It has been shown to influence the dif-
ferentiation and activation of certain immune cells, which are
crucial for mounting an effective immune response against viral
infections. By inhibiting PCSK9, it might be possible to fine-tune
the immune response, leading to a better-balanced reaction
against SARS-CoV-2 and potentially reducing the risk of immu-
nopathology. Research has shown that PCSK9 inhibitors play a
role in mitigating oxidative stress
[58]
. These inhibitors have been
found to reduce the production of ROS in atherosclerotic pla-
ques. This reduction in ROS production is significant because
ROS can contribute to the oxidation of LDL cholesterol, endo-
thelial dysfunction, and the activation of macrophages within the
arterial walls
[58]
. These processes are proatherogenic, meaning
they promote the development of atherosclerosis. Mitochondrial
DNA damage is another hallmark of oxidative stress. Damage to
mitochondrial DNA is often measured using specific markers like
8-OHdG, which is sensitive and specific to such damage. Studies
have shown that PCSK9 inhibitors are effective in reducing the
expression of 8-OHdG, indicating that they help protect mito-
chondrial DNA from oxidative damage
[59]
. This protection is
essential because damage to mitochondrial DNA can lead to
dysfunctional mitochondria, which, in turn, can further con-
tribute to oxidative stress and inflammation within the arterial
walls. Impaired autophagy has been associated with the wor-
sening of vascular plaques, increased oxidative stress, and
heightened inflammation
[60]
. When autophagy is compromised,
cells struggle to efficiently eliminate unwanted substances and
dysfunctional components, which can contribute to the devel-
opment of atherosclerosis
[60]
. This is because atherosclerosis
involves the accumulation of lipids, cellular debris, and inflam-
matory components within the arterial walls, which would typi-
cally be removed through effective autophagy. PCSK9 inhibitors
have shown promise in enhancing autophagy in vascular tissue
and macrophages, the immune cells within the arterial walls
[58]
.
This enhancement of autophagy is significant in the context of
atherosclerosis for several reasons. Autophagy plays a role in
breaking down lipids, which are a fundamental component of the
plaques that accumulate in atherosclerosis
[58]
. Enhanced autop-
hagy can help in degrading these lipids, potentially reducing
plaque formation. It also regulates inflammation. In athero-
sclerosis, inflammation contributes to plaque development. By
promoting autophagy, PCSK9 inhibitors may help control
inflammation within the arterial walls
[58,59]
. It is essential for
maintaining cellular health and function. When autophagy is
efficient, it can prevent cell damage and dysfunction, which are
common in atherosclerotic conditions. Autophagy helps prevent
the formation of macrophage foam cells, which are a key con-
tributor to plaque development. By enhancing autophagy in
macrophages, PCSK9 inhibitors may reduce the formation of
these foam cells
[58]
. The protective effects of PCSK9 inhibitors in
preventing atherosclerosis development are closely tied to their
ability to enhance autophagy. By facilitating the removal of
unwanted components, including lipids and inflammatory fac-
tors, they help maintain cellular health and reduce the conditions
that promote plaque accumulation within arterial walls.
Potential antiviral effects
Recent studies have suggested that PCSK9 might be involved in
the entry of certain viruses, including SARS-CoV-2, into host
cells
[61]
. By inhibiting PCSK9, it may be possible to interfere with
the virus’s entry process, limiting viral replication and spread.
However, the extent of PCSK9’s direct involvement in viral entry
and replication is still an area of ongoing research.
Beneficial effects on coagulation and thrombosis
Recent research has shed light on the potential role of PCSK9 in
modifying platelet function, a critical component of blood clot-
ting and the body’s response to vascular injury. Dyslipidemia,
characterized by abnormal lipid levels in the bloodstream, can
have a profound impact on the delicate balance of haemostasis
and platelet reactivity
[62]
. Elevated levels of LDL-C have been
linked to increased platelet reactivity and the heightened pro-
duction of thromboxane, a molecule that promotes blood clot
formation. Furthermore, high levels of circulating LDL-C are
associated with increased oxidative stress, a condition char-
acterized by the excessive production of ROS. This oxidative
stress significantly contributes to inflammation-driven thrombo-
sis, the pathological formation of blood clots within blood
vessels
[62]
. Oxidized LDL (oxLDL), a product of oxidative stress
due to high LDL-C concentrations, plays a central role in
increasing platelet activation via CD36, a receptor involved in
recognizing specific oxidized lipids and lipoproteins. CD36 is
essential for processes like the clearance of apoptotic cells,
responses to bacterial and fungal infections, and the uptake of
LDL
[62]
. Activation of CD36 by oxLDL triggers inflammatory
reactions that alter the progression of atherosclerosis, a condition
characterized by the buildup of plaque in the arteries.
Intriguingly, PCSK9 has been found to bind to CD36, which is a
negative regulator of angiogenesis. This interaction between
PCSK9 and CD36 results in the activation of platelets. However,
the use of PCSK9 inhibitors has been shown to decrease platelet
activity, mitigating their impact on thrombosis. Studies, such as
the PCSK9—REACT study, have established a link between
elevated PCSK9 levels and platelet activation, suggesting that
PCSK9 can serve as a predictor of ischaemic events
[63]
. Research
has demonstrated that PCSK9, through its interaction with the
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CD36 receptor, directly increases platelet activation and in vivo
thrombosis
[64]
. Additionally, treatment with PCSK9 inhibitors
has been shown to lead to reduced levels of LDL, oxLDL, and
PCSK9 in patients with familial hypercholesterolaemia, which
further supports the role of PCSK9 in platelet activation and
thrombosis
[65]
. Furthermore, PCSK9’s interaction with CD36
activates enzymes and signalling pathways that are associated
with the production of ROS, which can promote platelet activa-
tion and thrombosis. Some studies suggest that PCSK9 also plays
a role in regulating CD36 and triglyceride metabolism
[66]
.
Notably, PCSK9 inhibitors have been associated with a reduction
in venous thromboembolism risk. This risk reduction is asso-
ciated with baseline Lp(a) concentrations, suggesting that Lp(a)
can serve as a marker for observation
[67]
. Moreover, PCSK9
inhibitors have been found to impact factors related to platelet
activation and thrombosis, such as D-dimer, fibrinogen, and
plasminogen activator inhibitor-1 (PAI-1)
[68]
. Additionally, they
have been shown to raise HDL cholesterol levels, which can
indirectly prevent platelet aggregation by affecting platelet
membrane cholesterol. PCSK9 is also associated with cellular
apoptosis in vascular smooth muscle and endothelial cells. The
death of these cells can promote thrombosis through the pro-
duction of procoagulant microparticles
[69]
. Interestingly, plate-
lets have been found to secrete PCSK9 after activation in the
presence of LDL, which can enhance platelet aggregation and
thrombus formation.
Safety considerations
Safety considerations and possible risks are critical factors that
need to be carefully evaluated when considering the use of PCSK9
inhibitors in the context of COVID-19 or any other medical
condition. While PCSK9 inhibitors have shown promising results
in lipid management and potential benefits in other areas, it is
essential to understand and address potential safety concerns
before implementing them in clinical practice. PCSK9 inhibitors
are highly effective in reducing LDL cholesterol levels, which is
their primary intended effect. However, excessively low LDL
cholesterol levels could have unintended consequences.
Cholesterol is essential for various cellular functions, including
hormone synthesis and cell membrane integrity. Therefore,
careful monitoring of cholesterol levels and appropriate dose
adjustments are crucial to maintaining a balance between LDL
cholesterol reduction and overall health.
PCSK9 inhibitors can interact with other medications,
including immunosuppressants and anticoagulants, potentially
affecting their effectiveness or safety. Drug interactions should be
thoroughly evaluated, especially in COVID-19 patients receiving
multiple medications for their condition. Healthcare providers
should be cautious about potential interactions and adjust the
treatment plan accordingly.
Safety in Specific Populations: Special attention should be
given to the safety of PCSK9 inhibitors in specific populations,
such as pregnant or breastfeeding individuals, children, and
patients with severe liver or kidney impairment. The safety profile
of PCSK9 inhibitors may vary in these groups, and their use
should be approached cautiously, considering individual risks
and benefits. PCSK9 inhibitors are biological drugs that can
induce an immune response in some patients. This immuno-
genicity could potentially reduce the drug’s effectiveness over
time or lead to allergic reactions. Monitoring for any signs of
immune reactions or decreased efficacy is important to ensure
optimal patient outcomes. While PCSK9 inhibitors have
demonstrated favourable safety profiles in clinical trials, their
long-term safety in the context of COVID-19 or other chronic
conditions needs further investigation. Continuous monitoring
and post-marketing surveillance are essential to assess any
potential rare or long-term adverse events. PCSK9 inhibitors are
biological drugs and can be expensive, which may limit access for
some patients. The cost-effectiveness of these medications should
be carefully evaluated, considering potential benefits and risks.
PCSK9 inhibitors may influence the immune response, and this
could have implications for COVID-19 patients. It is essential to
understand how PCSK9 inhibition may affect the body’s ability
to respond to viral infections, especially in critically ill patients.
While PCSK9 inhibitors are designed to target PCSK9 specifi-
cally, there is always a possibility of off-target effects on other
proteins or biological pathways. Understanding these potential
off-target effects is critical for assessing the overall safety profile
of PCSK9 inhibitors. Although PCSK9 is primarily known for its
role in regulating lipid metabolism in the liver, recent research has
revealed its presence in non-hepatic tissues, including the brain.
There is emerging evidence that links PCSK9, both in terms of
protein levels and genetic variations within the PCSK9 gene, to
mood disorders and related traits, such as depressive symptoms
and neuroticism
[70]
. Mendelian randomization studies, which
utilize genetic risk scores based on PCSK9 gene variants, have
suggested an association between PCSK9 and an increased risk of
major depressive disorder, although not with neuroticism
[71]
.
These findings imply that PCSK9 may play a role in the devel-
opment of major depressive disorder. In vivo experiments have
also provided insights into the potential impact of PCSK9 on the
brain. Overexpression of LDLR, a protein targeted for degrada-
tion by PCSK9, in the brains of mice triggered neuroin-
flammatory responses, suggesting that inhibiting PCSK9 might
lead to neuroinflammation
[72]
.
Using PCSK9 inhibition as a therapeutic approach for COVID-
19 presents several challenges and potential limitations. As of my
last knowledge update in September 2023, clinical data sup-
porting its use were limited
[58]
. This lack of data means that the
clinical impact and safety of PCSK9 inhibitors for COVID-19
remain uncertain. COVID-19 is a multifaceted disease with var-
ious underlying mechanisms. PCSK9 inhibition might address
some aspects of the disease, but it is unlikely to serve as a com-
prehensive solution for all cases. The risk-benefit profile of
PCSK9 inhibitors for COVID-19 needs careful evaluation, con-
sidering that COVID-19 primarily affects the respiratory system
and may involve different pathways compared to their typical use
for lipid control. Like any medication, PCSK9 inhibitors can have
side effects, some of which may not be apparent when used for
cholesterol management. These potential side effects must be
taken into account. Cost and accessibility are crucial factors.
PCSK9 inhibitors can be expensive, and ensuring broad access
during a global pandemic could be challenging. The development
of PCSK9 inhibitors specifically for COVID-19 would require
rigorous testing and regulatory approvals, making the process
time-consuming and costly. COVID-19 strains vary, and the
effectiveness of a treatment may differ between strains. Ensuring
that PCSK9 inhibition works across various strains is vital for its
success in treating COVID-19.
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Future directions
Rigorous clinical trials are needed to assess the safety and efficacy
of PCSK9 inhibitors in COVID-19 patients, especially those at
high risk for severe outcomes. Large-scale randomized controlled
trials can help determine the impact of PCSK9 inhibition on
reducing inflammation, mitigating cardiovascular complications,
and improving overall survival in COVID-19 patients. Research
can focus on determining the optimal timing and dosage of
PCSK9 inhibitors during COVID-19 infection to achieve max-
imum benefits while minimizing potential risks. This may involve
studying different treatment regimens and their impact on lipid
metabolism, inflammation, and thrombosis in the context of the
disease. Investigating the potential benefits of combining PCSK9
inhibitors with other therapeutics used in COVID-19 manage-
ment, such as antiviral drugs and anticoagulants, can offer
synergistic effects and improved patient outcomes. Studies
exploring the safety and efficacy of combination therapies could
provide valuable insights. Understanding the impact of PCSK9
inhibition on the immune response in COVID-19 patients is
crucial. Further research can explore the effects of PCSK9 inhi-
bitors on immune cell function, viral clearance, and vaccine
responses to ensure that these medications do not compromise the
body’s ability to fight the infection. Long-term safety data are
essential to assess the potential risks associated with prolonged
PCSK9 inhibitor use. Observational studies and real-world evi-
dence can provide insights into any rare or delayed adverse events
and inform clinical practice guidelines. Identifying specific patient
subgroups that may benefit the most from PCSK9 inhibition in
COVID-19 or other conditions can enhance treatment precision.
Personalized medicine approaches can optimize treatment stra-
tegies and improve outcomes based on individual patient char-
acteristics and risk profiles. PCSK9’s role in inflammation,
immune modulation, and thrombosis is not yet fully understood.
Further research is needed to elucidate the molecular mechanisms
underlying these non-lipid-related functions, paving the way for
targeted therapeutic interventions. Beyond COVID-19, PCSK9
inhibitors have the potential to benefit patients with other
inflammatory and cardiovascular conditions. Research can
explore the safety and efficacy of PCSK9 inhibitors in diseases
such as atherosclerosis, rheumatoid arthritis, and other immune-
mediated disorders. Developing new PCSK9 inhibitors with
improved pharmacokinetic profiles, alternative routes of admin-
istration, and enhanced efficacy may offer additional treatment
options and expand the utility of PCSK9 inhibition in various
clinical scenarios. Conducting health economic analyses can
assess the cost-effectiveness of PCSK9 inhibitors in different
patient populations, helping policymakers make informed deci-
sions about resource allocation and reimbursement.
Conclusion
In conclusion, PCSK9 inhibition represents a compelling and
multifaceted area of research with potential implications in the
management of COVID-19 and other medical conditions. The
interplay between PCSK9 and various physiological processes,
including lipid metabolism, inflammation, and thrombosis, offers
a promising avenue for therapeutic intervention. In the context of
COVID-19, PCSK9 inhibitors hold promise for their potential to
attenuate the cytokine storm, protect against ARDS, and mitigate
cardiovascular complications. By reducing LDL cholesterol levels
and modulating immune and inflammatory responses, PCSK9
inhibition could play a role in improving patient outcomes and
potentially reducing the severity of the disease. However, it is
essential to approach the use of PCSK9 inhibitors in COVID-19
and other conditions with caution, considering potential safety
considerations and drug interactions. Rigorous clinical trials are
necessary to validate the efficacy and safety of PCSK9 inhibitors
in specific patient populations and to determine the optimal
timing and dosing of these medications.
Ethical approval
Ethics approval was not re AQ5
quired for this Review Article.
Consent
Informed consent was not required for this Review Article.
Sources of funding
The authors received no specific funding for this manuscript.
Author contribution
Concept: J.M., H.A., N.I., V.K., U.N.K. Data collection: C.P.K.,
F.P., H.A, Design: S.K., M.T.H., D.K., D.R., F.P. Data analysis:
S.K., A.M. Writing: C.P.K., F.P., H.A., S.K., M.T.H., D.K., D.R.,
F.P., S.K., J.M. Supervision: A.M., J.M.
Conflicts of interest disclosure
The authors have no conflict of interests.
Research registration unique identifying number
(UIN)
Not applicable.
Guarantor
Amin mehmoodi.
Data availability statement
Not applicable.
Provenance and peer review
Not invited.
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